Synthesis and uses of polymer gel nanoparticle networks

Abstract

Disclosed is a new class of nanostructured polymeric materials comprising polymer gel nanoparticles that are covalently bonded through functional groups on the surfaces of neighboring particles. These nanoparticles may be prepared as suspensions in an aqueous or, non-aqueous environment. These gels have two unique and different structural networks; the primary network comprises crosslinked polymer chains in each individual particle, while the secondary network is a system of crosslinked nanoparticles. Particular polymer gel nanoparticle network compositions disclosed herein may function as carriers for controlled delivery of pharmaceuticals or other chemical agents, gel sensors and other commercial applications.

What is claimed is:  
     
         1 . A nanostructured polymeric material comprising environmentally responsive nanoparticles, alone or in combination with non-environmentally responsive nanoparticles, that are bonded through functional groups on surfaces of neighboring particles to form a network.  
     
     
         2 . The nanostructured polymeric material of  claim 1 , wherein the network comprises two levels of structural difference; a primary network comprised of crosslinked polymer chains inside each nanoparticle and a secondary network comprising of a crosslinked system of the nanoparticles themselves.  
     
     
         3 . The nanostructured polymeric material of  claim 2 , wherein mesh size of the primary network is between 1-10 nm and the mesh size of the secondary network is between 50-500 nm.  
     
     
         4 . The nanostructured polymeric material of  claim 1  in which changes in the physical properties of the environmentally responsive nanoparticles such as hydrophobicity, volume change, and elasticity are brought about by changes in environmental conditions, including pH, temperature, electric current, ionic strength, type of solvent and pressure.  
     
     
         5 . The nanostructured polymeric material of  claim 1  further comprising N-isopropyl acrylamide or related analog, Hydroxypropylcellulose or related analog, polyvinyl alcohol or other analog, polypropylene oxide or related analog, polyethylene oxide, or related analog, polyethylene oxide/polypropylene oxide copolymers, or other known environmentally responsive polymer, alone or in combination thereof.  
     
     
         6 . The nanostructured polymeric material of  claim 1  further comprising nanoparticles in a particle size range of 1-1000 nanometers in diameter.  
     
     
         7 . The nanostructured polymeric material of  claim 1  further comprising nanoparticles in a particle size range of 1-1000 nanometers in diameter particle size range of 1-500 nanometers.  
     
     
         8 . The nanostructured polymeric material of  claim 1  further comprising nanoparticles in a particle size range of 1-1000 nanometers in diameter particle size range of 20-500 nanometers.  
     
     
         9 . The nanostructured polymeric material of  claim 1  comprising nanoparticles that are internally crosslinked with non-degradable or degradable crosslinking compounds and bonded through functional groups on surfaces of neighboring particles with non-degradable or degradable crosslinking compounds to form a network.  
     
     
         10 . The material of  claim 9  where the degradable crosslinking compounds have a monomeric or oligomeric composition comprising a polyacid with at least two acidic groups directly or indirectly connected to reactive groups usable to cross-link polymer filaments, wherein between at least one reactive group and the polyacid is a degradable sequence consisting of a hydroxyalkyl acid ester sequence having a number of hydroxyalkyl acid ester groups selected from the group consisting of 1, 2, 3, 4, 5 and 6; the cross-linker being usable to form cross-linked polymer filaments with defined degradation rates.  
     
     
         11 . The nanostructured polymeric materials of  claim 9  further containing at least one pharmaceutically active compound.  
     
     
         12 . The material of  claim 11  wherein said pharmaceutically active compound resides inside individual nanoparticles, between the nanoparticles or in both domains.  
     
     
         13 . The nanostructured polymeric material of  claim 11  used as a drug delivery device in vivo to treat a variety of wounds, diseases and disorders in humans and mammals.  
     
     
         14 . The nanostructured polymeric material of  claim 13  capable of providing a variety of controlled release rates of pharmaceutically active compounds through variations in the particle size of the nanoparticles composing the networks and/or biodegradable crosslinkers used in  claim 13 .  
     
     
         15 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises an anti-allergic agent.  
     
     
         16 . The nanostructured polymeric material of  claim 15 , wherein said anti-allergic agent is amlexanox, astemizole, azelastinep, emirolast, alopatadine, cromolyn, fenpiprane, repirinast, tranilast, or traxanox.  
     
     
         17 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises an anti-inflammatory analgesic agent.  
     
     
         18 . The nanostructured polymeric material of  claim 17 , wherein said anti-inflammatory analgesic agent is acetaminophen, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac, fenclofenac, clidanac, flubiprofen, fentiazac, bufexarnac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, or tiaramide hydrochloride.  
     
     
         19 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises an antianginal agent.  
     
     
         20 . The nanostructured polymeric material of  claim 19 , wherein said antianginal agent is nifedipine, atenolol, bepridil, carazolol, or epanolol.  
     
     
         21 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a steroidal anti-inflammatory agent.  
     
     
         22 . The nanostructured polymeric material of  claim 21 , wherein said steroidal anti-inflammatory agent is hydrocortisone acetate, predonisolone acetate, methylpredonisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flutetasone, fluormetholone, or beclomethasone diproprionate.  
     
     
         23 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises an antihistamine.  
     
     
         24 . The nanostructured polymeric material of  claim 23 , wherein said antihistamine is diphenhydramine hydrochloride, chlorpheniramine maleate, isothipendyl hydrochloride, tripelennamine hydrochloride, promethazine hydrochloride, or methdilazine hydrochloride.  
     
     
         25 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a local anesthetic.  
     
     
         26 . The nanostructured polymeric material of  claim 25 , wherein said local anesthetic is dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-buthylaminobenzoic acid, 2-(di-ethylamino) ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dyclonine, or dyclonine hydrochloride.  
     
     
         27 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a bactericide or disinfectant.  
     
     
         28 . The nanostructured polymeric material of  claim 27 , wherein said bactericide or disinfectant is thimerosal, phenol, thymol, benzalkonium chloride, chlorhexidine, povidone iodine, cetylpyridinium chloride, eugenol, trimethylammonium bromide, benzoic acid or sodium benzoate.  
     
     
         29 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a vasoconstrictor.  
     
     
         30 . The nanostructured polymeric material of  claim 29 , wherein said vasoconstrictor is naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, or tramazolinehydrochloride.  
     
     
         31 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a hemostatic agent.  
     
     
         32 . The nanostructured polymeric material of  claim 31 , wherein said hemostatic agent is thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbaxochrome sodium sulfate, rutin, or hesperidin.  
     
     
         33 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a chemotherapeutic agent.  
     
     
         34 . The nanostructured polymeric material of  claim 33 , wherein said chemotherapeutic agent is sulfamine, sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole, sulfisomidine, sulfamethizole, nitrofurazone, taxanes, platinum compounds, topoisomerase 1 inhibitors, or anthrocycline.  
     
     
         35 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises an antibiotic.  
     
     
         36 . The nanostructured polymeric material of  claim 35 , wherein said antibiotic is penicillin, meticillin, oxacillin, cefalotin, cefalordin, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, or clindamycin.  
     
     
         37 . The nanostructured polymeric material of  claim 1 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a keratolytic agent.  
     
     
         38 . The nanostructured polymeric material of  claim 37 , wherein said keratolytic agent is salicylic acid, podophyllum resin, podolifox, or cantharidin.  
     
     
         39 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a cauterizing agent.  
     
     
         40 . The nanostructured polymeric material of  claim 39 , wherein said cauterizing agent is chloroacetic acid or silver nitrate.  
     
     
         41 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a hormone.  
     
     
         42 . The nanostructured polymeric material of  claim 41 , wherein said hormone is estrone, estradiol, testosterone, equilin, or human growth hormone.  
     
     
         43 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises a growth hormone inhibitor.  
     
     
         44 . The nanostructured polymeric material of  claim 43 , wherein said growth hormone inhibitor is octreotide or somatostatin.  
     
     
         45 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compounds or combination of pharmaceutically active compounds comprises an analgesic narcotic.  
     
     
         46 . The nanostructured polymeric material of  claim 45 , wherein said analgesic narcotic is fentanyl, buprenorphine, codeine sulfate, levophanol, or morphine hydrochloride.  
     
     
         47 . The nanostructured polymeric material of  claim 11 , wherein said pharmaceutically active compound or combination of pharmaceutically active compounds comprises an antiviral drug.  
     
     
         48 . The nanostructured polymeric material of  claim 47 , wherein said antiviral drugs are protease inhibitors, thymadine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, attachment and adsorption inhibitors, and nucleoside analogues including acyclovir, penciclovir, valacyclovir, or ganciclovir.  
     
     
         49 . The nanostructured polymeric material of  claim 11 , wherein the pharmaceutically active compound or combination of pharmaceutically active compounds is between about 0.001 and about 30 percent by weight of the material.  
     
     
         50 . The nanostructured polymeric material of  claim 11 , wherein the pharmaceutically active compound or combination of pharmaceutically active compounds is between between about 0.005 and about 20 percent by weight of the material.  
     
     
         51 . The nanostructured polymeric material of  claim 1 , wherein the bonding of the nanoparticles together contributes to the structural stability of the network, while packing arrangement and size of the nanoparticles provide structures that can diffract light.  
     
     
         52 . The nanostructured polymeric material of  claim 51 , wherein said material is usable as an optical sensor using its environmentally responsive properties.  
     
     
         53 . The nanostructured polymeric material of claims  9  containing a chemical agent or combination of chemical agents other than a pharmaceutically active compound.  
     
     
         54 . The nanostructured polymeric material of  claim 53 , wherein the chemical agent is a pesticide, fungicide, fertilizer, or other agricultural material, a cationic, anionic, non-ionic exchange material or other complexing compound.  
     
     
         55 . A composition comprising the nanostructured polymeric material of  claim 1 .  
     
     
         56 . The composition of  claim 55 , formulated for bioremediation.  
     
     
         57 . The composition of  claim 55 , formulated as a mucoadhesive or a bioadhesive.  
     
     
         58 . The composition of  claim 55 , further comprising at least a first pharmaceutical excipient.  
     
     
         59 . The composition of  claim 58 , formulated for administration to an animal.  
     
     
         60 . The composition of  claim 58 , formulated for parental administration to an animal.  
     
     
         61 . A controlled-release pharmaceutical delivery system comprising the composition of  claim 55 , and at least a first diagnostic, therapeutic, or prophylactic medicament.  
     
     
         62 . The controlled-release pharmaceutical delivery system of  claim 61 , formulated for oral, intravenous, intraarterial, intradermal, subcutaneous, sublingual, inhalation, transdermal, intrathecal, intraossius, intranasal, intraocular, or intracellular administration.  
     
     
         63 . A therapeutic kit comprising the nanostructured polymeric material of  claim 1 , the composition of  claim 55 , or the controlled-release pharmaceutical delivery system of  claim 62 , and instructions for using said kit.  
     
     
         64 . The kit of  claim 63 , wherein said kit further comprises at least a first peptide, polypeptide, protein, vaccine, antisense oligonucleotide, hormone, growth factor, polynucleotide, vector, ribozyme, or at least a first diagnostic, therapeutic, or prophylactic medicament.  
     
     
         65 . A method of controlling the delivery of a pharmaceutical compound to a target site, said method comprising providing to said site, the controlled-release pharmaceutical delivery system of  claim 61 , for a time effective to deliver said compound to said site.  
     
     
         66 . A method of delaying or sustaining the delivery of a pharmaceutical compound to a first target site of a mammal, said method comprising administering to said mammal the controlled-release pharmaceutical delivery system of  claim 61 , in an amount and for a time effective to delay or sustain the delivery of said compound to said target site within said mammal.  
     
     
         67 . The method of  claim 66 , wherein said target site is a cell, tissue, gland, bone, tumor, or an organ within the body of said mammal.  
     
     
         68 . The method of  claim 66 , wherein said mammal is (a) a human, or (b) a non-human mammal under the care of a veterinarian.  
     
     
         69 . The method of  claim 66 , wherein said compound is delivered to said target site within a period of from about 10 min to about 24 hrs following administration of said pharmaceutical delivery system to said mammal.  
     
     
         70 . The method of  claim 66 , wherein said compound is delivered to said target site within a period of from about 20 min to about 12 hrs following administration of said pharmaceutical delivery system to said mammal.  
     
     
         71 . The method of  claim 66 , wherein said compound is delivered to said target site within a period of from about 30 min to about 6 hrs following administration of said pharmaceutical delivery system to said mammal.  
     
     
         72 . The method of  claim 66 , wherein said compound is delivered to said target site within a period of from about 1 hr to about 3 hrs following administration of said pharmaceutical delivery system to said mammal.  
     
     
         73 . A method of remediating a contaminated site, comprising contacting said site with, or providing to said site, an amount of the composition of  claim 55  effective to remediate said site.  
     
     
         74 . The method of  claim 73 , wherein said site is an environmental, commercial, residential or industrial site, or the site of an industrial accident.  
     
     
         75 . The method of  claim 73 , wherein said site comprises a radioactive, chemical, or biological contaminant.  
     
     
         76 . The method of  claim 73 , wherein said composition comprises a nanoparticle network that comprises at least a first functionalized moiety, or a free ionic charge on at least a first surface of said nanoparticle or said nanoparticle network.  
     
     
         77 . A bioadhesive material that comprises the composition of  claim 57 .  
     
     
         78 . The bioadhesive material of  claim 77 , comprising nanoparticles that comprise at least a first polymer selected from the group consisting of HPC, NIPA, PVA, PPO, PEO, PPO copolymer, and PEO.  
     
     
         79 . A method of preparing a nanostructured polymeric gel, comprising the steps of: 
 (a) contacting a plurality of polymeric gel nanoparticles under conditions effective to permit self-assembly of a substantial population of said polymeric gel nanoparticles into a network of nanoparticles; and    (b) reacting said network of nanoparticles with at least a first cross-linking agent under conditions effective to substantially covalently crosslink said network of nanoparticles to produce said nanostructured polymeric gel.    
     
     
         80 . The method of  claim 79 , wherein said crosslinking agent is a degradable crosslinking agent.  
     
     
         81 . The method of  claim 79 , wherein said crosslinking agent is a biodegradable crosslinking agent.  
     
     
         82 . The method of  claim 79 , wherein said crosslinking agent is divinyl sulfone.  
     
     
         83 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles comprises HPC, NIPA, PVA, PPO, PEO, PPO copolymer, or PEO copolymer nanoparticles.  
     
     
         84 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles comprises HPC.  
     
     
         85 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles comprises a population of internally-crosslinked nanoparticles.  
     
     
         86 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles comprises a population of nanoparticles internally-crosslinked using a non-degradable crosslinking agent.  
     
     
         87 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles comprises a population of colloidal nanoparticles.  
     
     
         88 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles are prepared by precipitation.  
     
     
         89 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles are prepared by precipitation from a solution that comprises at least a first surfactant.  
     
     
         90 . The method of  claim 89 , wherein said at least a first surfactant comprises DTAB.  
     
     
         91 . The method of  claim 89 , wherein said plurality of polymeric gel nanoparticles have an average particle size of from about 1 to about 5000 nm.  
     
     
         92 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles have an average particle size of from about 5 to about 2000 nm.  
     
     
         93 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles have an average particle size of from about 10 to about 1000 nm.  
     
     
         94 . The method of  claim 79 , wherein said plurality of polymeric gel nanoparticles have an average particle size of from about 50 to about 500 nm.